Drug for kidney failure containing oxaluric acid derivative

ABSTRACT

The effective ingredient of the agent for renal failure of the present invention is an oxaluric acid derivative having an excellent suppressive effect of the progression of renal failure. The oxaluric acid derivatives of the present invention have an excellent suppressive effect of the progression of renal failure to inhibit significantly the increase of creatinine level in blood accompanied by the progression of renal failure. The compounds of the present invention have highly safety with little side effects, so that they are very useful as an agent for renal failure which is required to be administered for long term.

TECHNICAL FIELD

The present invention relates to an agent for renal failure containingan oxaluric acid derivative or a pharmaceutically acceptable saltthereof as an effective ingredient.

BACKGROUND ART

In Japan, the number of chronic patients treated with hemodialysis istwo hundred nineteen thousand (at the end of 2001). The annualincreasing number of the patients run up to about thirteen thousand andis further increasing. Great efforts have been given to the prevention,early detection and treatment of renal failure, the suppression for theprogression of renal failure, and the supply and spread of medical careof hemodialysis and renal transplantation. The present inventors havecarried out investigations for a compound having high safety and beinguseful as an agent for renal failure, and have consequently found thatthe oxaluric acid derivatives of the present invention have asuppressive effect of the progression of renal failure whereupon thepresent invention has been accomplished. It has been known that theoxaluric acid derivatives of the present invention had hypoglycemiceffect (Japanese Examined Patent Publication Hei-06/60152). However,regarding the compounds of the present invention, the suppressive effectof the progression of renal failure has not been known at all.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a new agent for renalfailure with little side effects and high safety. As a result of theintensive investigations for oxaluric acid derivatives, the inventorshave found that they have excellent suppressive effects of theprogression of renal failure and are very useful as an agent for renalfailure whereupon the present invention has been accomplished.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows a result studying a suppressive effect of the creatinineincrease in blood, when the compound of the present invention,5-methyloxaluric acid, was administered to model rats of renal failure.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention relates to an agent for renal failure containingat least one oxaluric acid derivative represented by the general formula(I) or a pharmaceutically acceptable salt thereof as an effectiveingredient:

wherein each of R₁ and R₂, which may be the same or different, ishydrogen, an alkyl group or a cycloalkyl group, or R₁ and R₂ are joinedto form a heterocyclic ring with the nitrogen atom to which they areboth attached, and R₃ is hydrogen or an alkyl group.

In the above mentioned formula (I), each of R₁ and R₂, which may be thesame or different, is hydrogen, an alkyl group, preferably a straight orbranched alkyl group having 1 to 20 carbon atoms, such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, tert-pentyl, hexyl, dimethylbutyl, heptyl, octyl,nonyl, decyl or stearyl; a cycloalkyl group, preferably having 3 to 8carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl; or R₁ and R₂ are joined to form aheterocyclic ring with the nitrogen atom they are both attached to,preferably aziridino, pyrrolidino, piperidino, piperazino or morpholino.R₃ is hydrogen or an alkyl group, preferably a straight or branchedalkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, tert-pentyl, hexyl, dimethylbutyl, heptyl, octyl, nonyl,decyl or stearyl.

Preferred compounds of the present invention are indicated as follows:

-   5-methyloxaluric acid-   5-ethyloxaluric acid-   5-butyloxaluric acid-   5-isobutyloxaluric acid-   5-tert-butyloxaluric acid-   5-hexyloxaluric acid-   5-(1,3-dimethylbutyl)oxaluric acid-   5-decyloxaluric acid-   5-cyclopentyloxaluric acid-   5-cyclohexyloxaluric acid-   5-methyloxaluric acid ammonium salt-   5-ethyloxaluric acid ammonium salt-   5-methyloxaluric acid methyl ester-   5-methyloxaluric acid ethyl ester-   5-butyloxaluric acid methyl ester-   5-isobutyloxaluric acid ethyl ester-   5,5-dimethyloxaluric acid methyl ester-   5,5-dimethyloxaluric acid ethyl ester-   5-cyclohexyloxaluric acid ethyl ester-   5-cycloheptyloxaluric acid ethyl ester-   N-(1-piperidylcarbonyl)oxamic acid methyl ester-   N-(1-piperidylcarbonyl)oxamic acid ethyl ester-   5-methyloxaluric acid butyl ester-   5-methyloxaluric acid isobutyl ester-   5-methyloxaluric acid octyl ester-   5-butyloxaluric acid butyl ester-   5-cyclohexyloxaluric acid isopropyl ester-   5-cyclohexyloxaluric acid butyl ester

The oxaluric acid derivatives of the present invention includepharmaceutically acceptable salts of the compounds represented by theabove-mentioned formula (I) with alkali metal such as sodium orpotassium, with alkaline-earth metal such as calcium, magnesium orbarium, with other metal such as aluminium or zinc, with ammonium, withorganic amine or with acid. These salts can be prepared from freeoxaluric acid derivatives or other salts of the derivatives by knownmethods.

When there are steric isomers such as cis-trans isomer, optical isomerand conformational isomer, or hydrates and complexes of the compounds ofthe present invention, the present invention includes any of stericisomers, hydrates and complexes. The compounds of the present inventionand the methods for manufacturing them are disclosed in JapaneseExamined Patent Publication Hei-06/60152.

The compound of the present invention can be made into pharmaceuticalpreparations by a combination with a suitable pharmaceutical carriers ordiluents according to any conventional methods, for example,preparations for oral administrations (e.g. tablets, capsules, powders,liquids, etc.) and for parenteral administrations (e.g. forsubcutaneous, intravenous, intramuscular, intrarectal and intranasaladministrations). At preparing, the compound of the present inventionmay also be used in the form of the pharmaceutically acceptable salt,and can be used either solely or jointly together with otherpharmaceutically effective ingredients.

In the case of preparations for oral administration, the compound of thepresent invention as it is or together with commonly-used excipientssuch as suitable additives (e.g. lactose, mannitol, corn starch, potatostarch, potassium citrate, etc.) is mixed with binders such as cellulosederivatives (e.g. crystalline cellulose, hydroxypropylcellulose, etc.),gum arabicum, corn starch and gelatin, disintegrating agents such ascorn starch, potato starch and calcium carboxymethylcellulose,lubricants such as talc and magnesium stearate and other agents such asbulking agents, moisturizing agents, buffers, preservatives, perfumesand the like to give tablets, powders, granules or capsules.

In the case of injections, it is possible to prepare the solution,suspension or emulsion in aqueous solvents such as distilled water forinjection, physiological saline solution and glucose solution forinjection, or non-aqueous solvents such as plant oil, synthetic fattyacid glycerides, higher fatty acid esters and propylene glycol. Ifnecessary, conventional excipients such as solubilizing agents,isotonizing agents, suspending agents, emulsifiers, stabilizers andpreservatives may be added.

Furthermore, depending upon the type of the disease and patient, it ispossible to prepare other preparations than those which were mentionedalready, for example, suitable preparations for the therapy, such assuppositories, inhalations, aerosols, syrups, collyriums, medicines forexternal use (e.g. ointments), etc.

The preferred dose of the compound of the present invention may varydepending upon the patient to be administered, the preparation form, themethod and term of the administration, etc. In order to achieve adesired effect, 50-5,000 mg per day, preferably 100-3,000 mg per day maybe usually given to common adults by oral route. In the case ofparenteral administration such as by injection, since the effect may beexpected at parenteral administration by smaller dose than that of oraladministration, a dosage level of from ⅓ to 1/10 of the above given doseby oral administration may give the desired effect.

Preferred embodiments of the agent for renal failure containing thecompound represented by the above formula (I) as an effective ingredientare given as follows.

(1) An agent for renal failure containing the compound represented bythe formula (I), wherein R₃ represents hydrogen, as an effectiveingredient.

(2) The agent according to the above (1) containing the compounds,wherein R₂ represents hydrogen, as an effective ingredient.

(3) The agent according to the above (2) containing the compounds,wherein R₁ represents an alkyl group, as an effective ingredient.

(4) The agent according to the above (3) containing the compounds,wherein R₁ represents methyl, as an effective ingredient.

(5) The agent for renal failure containing 5-methyloxaluric acid or apharmaceutically acceptable salt thereof as an effective ingredient.

(6) The suppressive agent of the progression of renal failure containing5-methyloxaluric acid or a pharmaceutically acceptable salt thereof asan effective ingredient.

EXAMPLE 1 Suppressive Effect of the Progression of Renal Failure

Model animals of renal failure were prepared by oral administration ofadenine to male Wistar-strain rats (8 weeks age) [cf. Kidney andDialysis (extra number), p. 440-445 (1991); Nephron, vol. 44, p. 230-234(1986), etc.]. By daily administrations of adenine (200 mg/kg), thecreatinine level in blood as an indicator of renal function wasgradually increased from 0.44±0.02 mg/dL before administration to4.12+0.53 mg/dL after about 3 weeks. The creatinine clearance values(mL/kg/hr) were decreased from 315.3±13.8 to 25.7 ±4.4, and thus therenal function fell to about 1/10.

The compound of the present invention, 5-methyloxaluric acid, was orallyadministered to the adenine-induced renal failure rat at the dose of18.8 mg/kg or 37.5 mg/kg daily for 17 days from the 7th day after theadministration of adenine. The creatinine levels in blood were comparedbetween before and after administration of the test drug. The result ofthe suppressive effect of the test drug against creatinine increase (ΔCr) accompanied by the progression of renal failure is shown in FIG. 1.Five rats were used as a group for the test. The average value±standarderror was calculated and the significant difference between the testdrug group and the diseased control group was statistically analyzed bymeans of Dunnett's test (*; p<0.05).

EXAMPLE 2 Single Dose Toxicity Test

5-Methyloxaluric acid was intravenously administered to SD-strain rats(6 weeks age, 5 males and 5 females) at the dose of 75 to 600 mg/kg. Asa result, even at the dose of 600 mg/kg, any abnormalities of generalsymptoms, body weight and autopsies are observed and, as a matter ofcourse, there is no death.

INDUSTRIAL APPLICABILITY

It is apparent from the above-mentioned pharmacological tests that thecompounds of the present invention significantly suppressed the increaseof creatinine levels in blood accompanied by the progression of renalfailure. Moreover, no toxicities were observed in the single dosetoxicity test using rats. As above-mentioned, the compounds of thepresent invention exhibit an excellent suppressive effect of theprogression of renal failure and have high safety with little sideeffects, so that they are very useful as an agent for renal failurewhich is required to be administered for long term.

1. (canceled)
 2. The agent for renal failure according to claim 1,wherein the agent is a therapeutic or preventive agent for renalfailure.
 3. The agent for renal failure according to claim 2, whereinthe agent is a therapeutic or preventive agent for acute renal failure.4. The agent for renal failure according to claim 2, wherein the agentis a therapeutic or preventive agent for chronic renal failure.
 5. Anagent for renal failure according to claim 1, wherein the agent is asuppressive agent for the progression of renal failure.
 6. A method forsuppressing the progression of renal failure comprising administering toa patient in need of such suppression a pharmaceutically effectiveamount of at least one oxaluric acid derivative represented by thefollowing formula (I) or a pharmaceutically acceptable salt thereof asan effective ingredient:

wherein each of R₁ and R₂, which may be the same or different, ishydrogen, an alkyl group or a cycloalkyl group, or R₁ and R₂ are joinedto form a heterocyclic ring with the nitrogen atom to which they areboth attached, and R₃ is hydrogen or an alkyl group.
 7. A method asclaimed in claim 6 wherein R₃ is hydrogen.
 8. A method as claimed inclaim 6 wherein R₂ is hydrogen.
 9. A method as claimed in claim 6wherein R₁ is an alkyl group.
 10. A method as claimed in claim 9 whereinR₂ is hydrogen and R₃ is an alkyl group.
 11. A method as claimed inclaim 6 wherein R₃ is an alkyl group.
 12. A method as claimed in claim11 wherein R₁ is a cycloalkyl group.
 13. A method as claimed in claim 11wherein R₁ and R₂ are joined to form a heterocyclic ring with thenitrogen atom to which they are both attached.
 14. A method as claimedin claim 6 wherein said at least one oxaluric acid derivative comprises5-methyloxaluric acid.
 15. A method as claimed in claim 6 wherein therenal failure is acute renal failure.
 16. A method as claimed in claim 6wherein the renal failure is chronic renal failure.
 17. A method forsuppressing the level of creatinine in blood comprising administering toa patient in need of such suppression a pharmaceutically effectiveamount of at least one oxaluric acid derivative represented by thefollowing formula (I) or a pharmaceutically acceptable salt thereof asan effective ingredient:

wherein each of R₁ and R₂, which may be the same or different, ishydrogen, an alkyl group or a cycloalkyl group, or R₁ and R₂ are joinedto form a heterocyclic ring with the nitrogen atom to which they areboth attached, and R₃ is hydrogen or an alkyl group.
 18. A method asclaimed in claim 17 wherein the increase of the creatinine level inblood accompanied by the progression of renal failure is suppressed. 19.A method as claimed in claim 17 wherein the renal failure is acute renalfailure.
 20. A method as claimed in claim 17 wherein the renal failureis chronic renal failure.
 21. An agent for renal failure containing atleast one oxaluric acid derivative represented by the following formula(I) or a pharmaceutically acceptable salt thereof as an effectiveingredient:

wherein each of R₁ and R₂, which may be the same or different, ishydrogen, an alkyl group or a cycloalkyl group, or R₁ and R₂ are joinedto form a heterocyclic ring with the nitrogen atom to which they areboth attached, and R₃ is hydrogen or an alkyl group.